This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Compared to the traditional cyclic regimen, continuous combined oral contraceptives (COCs) decrease the overall number of scheduled bleeding days (Miller and Hughes, 2003). However, they are associated with irregular bleeding and spotting (Anderson and Hait, 2003). This represents a major nuisance to women and may lead to method discontinuation and unplanned pregnancy. Currently there are no preventative methods or treatment options for unscheduled bleeding associated with continuous COCs. The main objectives in this study are to: (1) determine whether typical dose doxycycline (100 mg BID) taken for five days can be used to decrease the duration of bleeding episodes and (2) determine whether Controlled-Release Sub-antimicrobial (CRSD) doxycycline (40 mg) can prevent bleeding episodes or decrease the number of days of unscheduled bleeding in women using continuous COCs. Secondary objectives are to: (1) document the safety and side effect profile of typical dose doxycycline (100 mg) and CRSD doxycycline when taken with a continuous COC and (2) explore subject satisfaction and compliance with COCs when taken with these doxycycline formulations. We intend to conduct a prospective, randomized, placebo controlled, double blind study at Oregon Health and Science University (OHSU) and John A. Burns School of Medicine (JABSOM). This study will be conducted over four 28-day cycles (112 days of active COC hormone). All women enrolled in the study will take the same daily low dose COC. This protocol is divided into two studies, a bleeding study and an endometrial biopsy study, each with two treatment arms;typical dose doxycycline (Arm 1), and CRSD (Arm 2). Only the bleeding study will be conducted at JABSOM. The first arm (Arm 1) of this study will constitute the typical dose doxycycline arm. In this arm, there will be two study groups. Group 1, the treatment group, will take doxycycline 100 mg orally twice a day for five days starting on the first day of bleeding if breakthrough bleeding occurs. The control group (Group 2) will take a placebo orally twice a day for five days starting on the first day of bleeding if breakthrough bleeding occurs. After three months, both groups will stop doxycycline (or placebo) and will continue on a COC alone for the remaining 28 days of the study. The second arm (Arm 2) of the study will constitute the CRSD doxycycline arm. Subjects in this arm of the study will be divided into Group 3 and Group 4. Group 3 will take CRSD doxycycline (40mg) daily for three months. Group 4 will take a daily placebo. Similarly to the first arm of the trial, after three months, both groups will stop doxycycline (or placebo) and will continue on a COC alone for the remaining 28 days of the study.